Causes of hypercalcemia
Parathyroid disease
Drugs
Adenoma
Lithium
Hyperplasia
Thiazide diuretics
MEN 1, MEN 2A
Vitamin D toxicity
Secondary hyperparathyroidism
Vitamin A toxicity
Tertiary hyperparathyroidism
Aminophylline
Carcinoma
Miscellaneous
Hyperparathyroidism-jaw tumor syndrome
Familial hypocalciuric hypercalcemia
Familial isolated hyperparathyroidism
Milk alkali syndrome
Malignancy
Granulomatous diseases
Ectopic PTH secretion
Immobilization
Parathyroid hormone-related protein
Lytic bone lesions
Ectopic vitamin D
Endocrine
Hyperthyroidism
Adrenal insufficiency
Pheochromocytoma
Familial hypocalciuric hypercalcemia (FHH), which is due to abnormalities in the calcium-sensing receptor (CaSR) in the parathyroid glands and kidneys, may cause both elevated calcium and PTH levels. This rare benign disorder does not require treatment and should be excluded prior to any surgical intervention. Patients may be screened with a calcium/creatinine clearance ratio (CCCR). Patients with FHH typically have a CCCR of less than 0.01, while those with PHPT have a ratio greater than 0.02. However, there is a great degree of overlap of these two diseases in patients with CCCRs between 0.01 and 0.02. Thus, those with a CCCR in this range may benefit from CaSR mutational analysis to clearly establish the diagnosis.
Preoperative Imaging
Minimally invasive parathyroid surgery, in which fewer than four glands are sought, relies on identification of the likely abnormal gland location with preoperative imaging. This helps direct the surgeon to the side most likely to contain the abnormal gland and can offer information as to whether a superior or inferior gland is involved or if an ectopic adenoma is present. Studies suggest that performing at least two different imaging modalities can improve tumor localization and, when concordant, may result in successful surgery in 97 % of patients undergoing minimally invasive parathyroidectomy. It is important to recognize that these imaging modalities are not used to diagnose parathyroid disease but rather to help guide the surgeon in selecting the most appropriate procedure once the diagnosis is confirmed biochemically.
Technetium-99m sestamibi (sestamibi) is the most common imaging modality currently used (Fig. 16.1). The agent is concentrated in both the thyroid and parathyroid glands but takes longer to wash out of the parathyroid glands due to the relatively high mitochondrial content within parathyroid cells. The sensitivity of sestamibi varies between 50 and 90 % depending on the institution. The sensitivity may drop in the presence of thyroid nodules, which are found in more than a third of all patients that are imaged. A negative sestamibi does not necessarily preclude treatment with a minimally invasive procedure. This modality may be of limited use in detecting small adenomas, and the accuracy may vary based on calcium and PTH levels, patient body mass index, or in patients taking calcium channel blockers. Ultrasound or another imaging modality may identify the single adenoma and therefore render the patient a candidate for a minimally invasive procedure. However, a negative sestamibi may impart a higher risk of multigland disease, up to 47 % in some series, so the surgeon should be prepared to perform a bilateral exploration in these patients if necessary.
Fig. 16.1
Second phase of technetium-99m sestamibi scan obtained at 2 h showing uptake consistent with a left inferior parathyroid adenoma
Sestamibi is useful in detecting ectopic parathyroid glands, identifying up to 75 % of cases in one series. The test is often combined with single photon emission computed tomography (SPECT) to improve anatomic localization of a sestamibi-positive lesion. Sestamibi-SPECT has also been shown to improve single adenoma detection compared with standard planar sestamibi techniques and has an overall sensitivity of 78.9 %. Sestamibi-SPECT is now routinely performed as the initial imaging modality in many institutions and is recommended in all cases of previously failed surgery.
Ultrasound using a high-frequency linear array transducer is also frequently used to evaluate the parathyroid glands preoperatively and has an overall sensitivity of 76 % for single-gland disease. It is often combined with a sestamibi scan, which increases detection sensitivity to 89–98 %. There are many advantages of ultrasound, including the speed and accessibility of the procedure, a relatively low cost, and the lack of radiation exposure. Perhaps the most important advantages are the ability of the surgeon to personally perform the study and visualize the anatomic location of the adenoma and the opportunity to evaluate for the presence of any concurrent thyroid disease, such as nodules or thyroiditis, which may significantly affect surgical planning.
Normal parathyroid glands are typically not appreciated on cervical ultrasound. Parathyroid adenomas usually present as round or ovoid solid hypoechoic masses. They are generally separated from the thyroid gland by an echogenic band. The presence of a polar vascular pedicle on Doppler mode rather than a central hilar vascular pattern can help distinguish adenomas from lymph nodes. Ultrasound will typically detect eutopic glands larger than 1 cm, but its sensitivity decreases in the presence of multigland disease, when the glands are usually not as large as in the case of single-gland adenomas. Ultrasound may visualize the location of some ectopic gland locations in the neck, such as an intrathyroidal adenoma, but its utility is limited in cases of mediastinal or retropharyngeal lesions.
Computed tomography (CT) and magnetic resonance imaging (MRI) have been used to provide cross-sectional anatomic imaging of abnormal parathyroid glands. The utilization of these modalities has traditionally been limited because of their use of contrast, decreased sensitivity, and significant radiation exposure (with CT). Therefore, these studies have primarily been reserved for cases with unsuccessful localization with ultrasound and sestamibi, ectopic glands, and reoperative procedures. The development of advanced imaging techniques such as 4D-CT, in which contrast uptake and washout are combined with CT imaging to identify parathyroid lesions, may contribute to improved imaging accuracy and help identify cases of multigland disease.
Medical Treatment
Though surgery is the only cure for PHPT, there are patients who may not be candidates for the procedure. These may be asymptomatic individuals who do not yet meet the established guidelines for surgical intervention or who may have other medical comorbidities that place them at high risk of a perioperative adverse event. Nonsurgical options include surveillance with regular evaluation by a primary care physician or endocrinologist, correction of any underlying vitamin D deficiency, a normocalcemic diet, and medical intervention. Agents potentially useful in the treatment of PHPT include bisphosphonates, hormone replacement therapy in postmenopausal women, or the use of calcimimetics. Bisphosphonates and hormone replacement therapy may help decrease bone turnover and improve bone mineral density, but have not been shown to durably reduce PTH or calcium levels. Calcimimetics, such as cinacalcet, modulate the CaSR, increasing the receptor’s sensitivity to circulating calcium and thereby decreasing PTH release. Cinacalcet may decrease calcium and PTH levels, but does not significantly improve bone density. It is important that patients be counselled that medical treatment may help mediate some of the metabolic effects of their condition, but does not cure them of their disease.
Surgical Intervention
Indications
Surgery is the only curative treatment for PHPT and is more cost effective than prolonged medical therapy. Parathyroid surgery is indicated in patients with symptomatic hyperparathyroidism or in asymptomatic patients who meet the guidelines established by the 2002 and 2009 NIH consensus panels (Table 16.2). Patients with non-localizing imaging studies or those with disorders known to involve multiple glands generally undergo a bilateral neck exploration.
Table 16.2
Indications for parathyroidectomy
Indications for parathyroidectomy in asymptomatic patients | |
|---|---|
1. Serum calcium elevated more than 1 mg/dL above upper limits of normal | 4. Age <50 years old |
2. Glomerular filtration rate <60 mL/min | 5. Patient requests surgery or is poor candidate for long-term observation |
3. Bone mineral density T-score <−2.5 at any site or prior fragility fracture | |
Candidates for successful minimally invasive non-endoscopic parathyroid surgery are patients with presumed single-gland disease, who have localizing preoperative imaging studies. However, it is critical for surgeons to be aware that even in cases with concordant preoperative imaging studies, multiglandular disease can be present. The surgeon should therefore always be prepared to convert to a bilateral exploration if indicated.
Surgery
Traditional parathyroid surgery requires a long transverse neck incision (typically 7–10 cm), elevation of subplatysmal flaps, and bilateral neck exploration to expose all four parathyroid glands. Glands that appear abnormal are removed. Some surgeons confirm the presence of hypercellular tissue in the suspicious gland by comparing it to frozen section biopsy specimens from the normal-appearing glands. Drains are often placed and patients are typically admitted to the hospital for postoperative monitoring. This approach, with a success rate of 95 %, was considered the standard of care prior to widespread use of preoperative localization studies. It remains the standard by which the effectiveness of all minimally invasive approaches is judged. Bilateral exploration is still indicated in patients with disease entities associated with diffuse hyperplasia, such as renal hyperparathyroidism, MEN-1, and MEN-2A.
Though diverse in execution and the use of ancillary aids, minimally invasive parathyroid surgery is defined by a reduction either in the size of the incision or in the overall extent of dissection and resultant tissue trauma. Minimally invasive non-endoscopic parathyroidectomy utilizes a small incision, with initial dissection focused solely in the quadrant of the presumed abnormal gland (as seen on preoperative imaging). The procedure is subsequently directed by intraoperative findings and the results of the rapid intraoperative PTH (IOPTH) assay.
The planned cervical incision is marked while the patient is awake and upright in the holding area. This helps ensure the incision will be concealed within a naturally occurring skin crease (Fig. 16.2). The patient is placed supine on the operating table and general anesthesia is induced. Intubation is generally performed with a standard endotracheal tube, though in selected or revision cases a laryngeal EMG endotracheal tube (Medtronic ENT, Jacksonville, FL) may be used. Generally no shoulder roll is required, but the headrest of the bed is lowered slightly to provide gentle neck extension. The operating table is then rotated 180° so the patient’s lower extremities are facing the anesthesia team. This allows placement of an intravenous line in one of the patient’s feet for IOPTH assessment and obviates the need for an arterial line. An ultrasound repeated at this time by the surgeon can confirm the findings of the preoperative studies and provide precise guidance for the upcoming dissection. The planned incision site is infiltrated with 0.25 % bupivacaine with 1:200,000 epinephrine (Hospira, Lake Forest, IL), and a sterile prep is applied to the neck. A baseline IOPTH level is drawn prior to incision. The IOPTH assay is preferably performed by a technician with mobile equipment in the operating room, eliminating the transport time required to send the sample to the main laboratory (Fig. 16.3).
Fig. 16.2
Planned 1.5-cm midline incision in a naturally occurring skin crease
Fig. 16.3
Mobile intraoperative PTH assay equipment in operating room
A knife is used to make a 2- to 2.5-cm skin incision, and the dissection is carried through the subcutaneous tissue. Careful attention is given to absolute hemostasis, as any bleeding from superficial tissue layers can obscure critical visualization of deeper structural details. The medial aspects of the platysma, if encountered, are divided to the lateral extent of the incision. No subplatysmal flaps are elevated. The strap muscles are separated vertically in the midline and the thyroid isthmus is identified. The strap muscles on the side of the suspected adenoma are bluntly elevated off the anterior and lateral aspect of the thyroid lobe and secured under Terris thyroid retractors (Medtronic ENT, Jacksonville, FL).
Attention is then directed toward the most likely location of the pathologic gland, as predicted by localization studies. The majority of parathyroid adenomas lie in predictable locations within the central neck compartment, but up to 13 % of patients have supernumerary glands, which may be pathologic, and as many as 11 % of patients have more than 1 adenoma. The superior glands are usually located within a 2-cm area whose center is 1 cm cranial to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The location of the inferior parathyroid glands is more variable. They are typically located within 1 cm of the inferior aspect of the thyroid gland, anterior to a coronal plane drawn through the recurrent laryngeal nerve, but may be intimately associated with the thymus or thyrothymic tract in up to 26 % of patients.
To explore the superior gland, the thyroid lobe is retracted ventrally and medially with the Terris retractors, exposing the posterior aspect of the thyroid lobe and the paratracheal region. This exposure can usually be accomplished without division of the middle thyroid vein. The inferior parathyroid gland may be found by gently dissecting the soft tissue ventral to inferior pole of the thyroid gland or may be identified dorsal to the gland by gentle retraction of the thyroid lobe.
The ability to visually distinguish a normal from abnormal gland is crucial to minimally invasive parathyroid surgery, as there are often no normal glands exposed for reference. Normal parathyroid glands are typically flat, are light brown to tobacco in color, and are 3–8 mm long with an average weight of 40 mg. They are usually surrounded by or capped with fat (Fig. 16.4). Parathyroid adenomas are typically larger, more rounded, rubbery, and a darker red brown in color (Fig. 16.5). Gentle spreading of overlying fat may help reveal the enlarged glands. Once identified, blunt dissection with spatulas is used to gently liberate the gland from the surrounding soft tissue, until only the vascular pedicle remains attached to the gland. Soft tissue adherent to the capsule of the gland may be gently grasped to facilitate retraction and dissection, but care should be taken to avoid grabbing or excessive manipulation of the gland itself, as this may stimulate release of stored parathyroid hormone and alter subsequent IOPTH levels.
